W. Levin, A. Wood, R. Chang
Nov 1, 1980
Citations
1
Influential Citations
77
Citations
Quality indicators
Journal
Cancer research
Abstract
Abstract Benzo( c )phenanthrene [B(c)Ph], its three metabolically possible trans -dihydrodiols, and the diastereomeric bay-region diol-epoxides derived from trans -3,4-dihydroxy-3,4-dihydrobenzo( c )phenanthrene were tested for tumor-initiating activity on mouse skin. A single topical application of 0.4 or 2.0 µmol of compound was followed seven days later by twice-weekly applications of the tumor promotor 12- O -tetradecanoylphorbol-13-acetate for 20 weeks. B(c)Ph was found to be a weak tumor initiator on mouse skin, producing a 17 to 38% tumor incidence and 0.17 to 0.59 papilloma/mouse at the 0.4- and 2.0-µmol doses, respectively. Of the three metabolically possible trans -dihydrodiols of B(c)Ph, only trans -3,4-dihydroxy-3,4-dihydrobenzo( c )phenanthrene had significant tumor-initiating activity at the doses tested. This compound produced a 28 to 47% tumor incidence and 0.41 to 1.07 tumors/mouse at the 0.4- and 2.0-µmol doses, respectively. Comparisons of the number of papillomas observed per mouse indicated that both diastereomeric 3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo( c )phenanthrenes in which the epoxide oxygen is either cis (diol-epoxide 1) or trans (diol-epoxide 2) to the benzylic 4-hydroxyl group were at least 40-fold more tumorigenic than was the parent hydrocarbon. The bay-region diol-epoxides of B(c)Ph produced 6.5 to 7.0 papillomas/mouse at the 0.4-µmol dose, and the first appearance of tumors was observed as early as six weeks after the beginning of promotion. This is the first example of high tumorigenic activity for a bay-region diol-epoxide 1 diastereomer of a polycyclic aromatic hydrocarbon, and both diastereomeric bay-region diol-epoxides of B(c)Ph are more potent tumor initiators than are the bay-region diol-epoxides derived from benzo( a )pyrene and benzo( a )anthracene. Two model compounds, 1,2-dihydrobenzo( c )phenanthrene and trans -3,4-dihydroxy-1,2,3,4-tetrahydrobenzo( c )phenanthrene, which cannot be metabolized to bay-region diol-epoxides of B(c)Ph, were found to be inactive as tumor initiators on mouse skin. These results support the concept that a bay-region diol-epoxide is a prime candidate for an ultimate carcinogenic metabolite of B(c)Ph.